A cost-reducing extracorporeal membrane oxygenation (ECMO) program model: a single institution experience.

BACKGROUND: The worldwide demand for ECMO support has grown. Its provision remains limited due to several factors (high cost, complicated technology, lack of expertise) that increase healthcare cost. Our goal was to assess if an intensive care unit (ICU)-run ECMO model without continuous bedside perfusionists would decrease costs while maintaining patient safety and outcomes. METHOD: A new ECMO program was implemented in 2010, consisting of dedicated ICU multidisciplinary providers (ICU-registered nurses, mid-level providers and intensivists). In year one, we introduced an education platform, new technology and dedicated space. In year two, continuous bedside monitoring by perfusionists was removed and new management algorithms designating multidisciplinary providers as first responders were established. The patient safety and cost benefit from the removal of the continuous bedside monitoring of the perfusionists of this new ECMO program was retrospectively reviewed and compared. RESULTS: During the study period, 74 patients (28 patients in year 1 and 46 patients in year 2) were placed on ECMO (mean days: 8 ± 5.7). The total annual hospital expenditure for the ECMO program was significantly reduced in the new model ($234,000 in year 2 vs. $600,264 in year 1), showing a 61% decrease in cost. This cost decrease was attributed to a decreased utilization of perfusion services and the introduction of longer lasting and more efficient ECMO technology. We did not find any significant changes in registered nurse ratios or any differences in outcomes related to ICU safety events. CONCLUSION: We demonstrated that the ICU-run ECMO model managed to lower hospital cost by reducing the cost of continuous bedside perfusion support without a change in outcomes.

Veno-venous extracorporeal membrane oxygenation using a double-lumen bi-caval cannula for severe respiratory failure post total artificial heart implantation.

We report a unique utilization of a double-lumen, bi-caval Avalon cannula for veno-venous (VV) extracorporeal membrane oxygenation (ECMO) during placement of a total artificial heart (TAH, SynCardia, Tucson, AZ). A 22-year-old female with post-partum cardiomyopathy was rescued on veno-arterial (VA) ECMO because of cardiogenic shock. The inability to wean ECMO necessitated implantation of the TAH as a bridge to transplant. In addition, the patient continued to have respiratory failure and concomitant VV ECMO was planned with the implant. During TAH implantation, the Avalon cannula was placed percutaneously from the right internal jugular vein into the inferior vena cava (IVC) under direct vision while the right atrium was open. During VV ECMO support, adequate flows on both ECMO and TAH were maintained without adverse events. VV ECMO was discontinued, without reopening the chest, once the patient's respiratory failure improved. However, the patient subsequently developed a profound respiratory acidosis and required VV ECMO for CO2 removal. The Avalon cannula was placed in the femoral vein to avoid accessing the internal jugular vein and risking damage to the TAH. The patient's oxygenation eventually improved and the cannula was removed at the bedside. The patient was supported for 22 days on VV ECMO and successfully weaned from the ventilator prior to her orthotropic heart transplantation.

Successful management of bleeding complications in patients supported with extracorporeal membrane oxygenation with primary respiratory failure.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a lifesaving procedure in patients with severe respiratory insufficiency failing conventional support. Bleeding complications are common due to the necessity for anticoagulation and circuit-related factors. METHODS: A retrospective review was conducted in patients requiring ECMO for respiratory failure from 7/2010 to 6/2011 to identify episodes of major bleeding, bleeding management and outcomes. RESULTS: Twenty-one patients were supported with ECMO during the study although five experienced massive bleeding related to chest tube insertion, jejunal arterio-venous malformations, distal perfusion cannula dislodgement and ventricular rupture. Patients required aggressive resuscitation or endoscopic or operative intervention, totaling 28 procedures. There were no instances of dehiscence, infection or sepsis related to interventions. Anticoagulation was stopped six hours before and restarted 24 hours after major interventions, with no thrombotic or neurologic complications. All patients weaned off ECMO were discharged. CONCLUSIONS: ECMO bleeding complications can be managed successfully via surgical and endoscopic approaches in this high-risk population.

Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population.

AIMS/HYPOTHESIS: Recently, rs10906115 in CDC123/CAMK1D, rs1359790 near SPRY2, rs1436955 in C2CD4A/C2CD4B and rs10751301 in ODZ4 were identified as genetic risk variants for type 2 diabetes by a genome-wide association study in a Chinese population. The aim of the present study was to ascertain the role of these four variants in conferring susceptibility to type 2 diabetes in the Japanese population. METHODS: We genotyped 11,530 Japanese individuals (8,552 type 2 diabetes cases, 2,978 controls) for the above single nucleotide polymorphisms (SNPs) and used logistic regression analysis to determine whether they were associated with type 2 diabetes. RESULTS: In accordance with the findings in a Chinese population, rs10906115 A, rs1359790 C and rs1436955 G were found to be risk alleles. Both rs10906115 and rs1359790 were significantly associated with susceptibility to type 2 diabetes in our study (rs10906115 OR 1.15, 95% CI 1.08, 1.22; p = 6.10 × 10(-6); rs1359790 OR 1.14, 95% CI 1.06, 1.21; p = 2.24 × 10(-4)). Adjustment for age, sex and BMI had no significant effects on the association between these variants and the disease. We did not observe any significant associations between the SNPs and any metabolic traits, e.g. BMI, fasting plasma glucose (determined for 1,332 controls), HOMA of beta cell function (900 controls) and HOMA of insulin resistance (900 controls; p > 0.05). CONCLUSIONS/INTERPRETATION: The SNPs rs10906115 A and rs1359790 C are significantly associated with susceptibility to type 2 diabetes in the Japanese population, confirming that these alleles are common susceptibility variants for type 2 diabetes in East Asian populations.

Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6,244 Japanese individuals.

AIMS/HYPOTHESIS: Additional susceptibility loci for type 2 diabetes have been identified by a meta-analysis of genome-wide association studies (GWASs) in European populations. To examine further the roles of these new loci, we performed a replication study for the association of these single-nucleotide polymorphism (SNP) loci with the disease in three independent Japanese populations. METHODS: We genotyped seven of the 11 SNPs that emerged in stage 2 of the meta-analysis for European GWASs (rs864745 in JAZF1, rs12779790 near CDC123/CAMK1D, rs7961581 near TSPAN8/LGR5, rs4607103 near ADAMTS9, rs10923931 in NOTCH2, rs1153188 near DCD and rs9472138 near VEGFA) for three independent Japanese populations (first set, 1,630 type 2 diabetes patients vs 1,064 controls; second set, 1,272 type 2 diabetes patients vs 856 controls; third set, 486 type 2 diabetes patients vs 936 controls) using a TaqMan assay. The association of the SNP loci in each population was analysed using a logistic regression analysis, adjusting for age, sex and BMI, and the data were evaluated by a meta-analysis. RESULTS: A meta-analysis for the three case-control studies identified a nominal association of rs864745 in JAZF1 with type 2 diabetes (OR 1.148, 95% CI 1.034-1.275, p = 0.0098, corrected p = 0.069). The association of other loci did not reach statistically significant levels (nominal p > 0.05). CONCLUSIONS/INTERPRETATION: From these results the contribution of these seven loci in conferring susceptibility to type 2 diabetes is considered minor in the Japanese population, if they are present.

Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis.

BACKGROUND: TRIB3 is a human homologue of Drosophila tribbles. Previous studies have shown that TRIB3 controls the cell growth through ubiquitination-dependent degradation of other proteins, whereas its significance in the prognosis of colorectal cancer (CRC) is not yet fully understood. MATERIALS: This study comprised 202 patients who underwent surgery for CRC, as well as 22 cell lines derived from human gastrointestinal cancer. The correlation of gene expression with clinical parameters in patients was assessed. The biological significance was evaluated by knockdown experiments in seven colorectal cancer cell lines. RESULTS: A total of 20 cancer cell lines (90.9%) expressed the TRIB3 gene. The assessment in surgical specimens indicated that the gene expression was significantly higher in the cancerous region than in the marginal non-cancerous region. Patients with high TRIB3 expression were statistically susceptible to a recurrence of the disease, and showed poorer overall survival than those with low expression. The assessment of TRIB3 knockdown in five cell lines showed that small interfering RNA (siRNA) inhibition resulted in a statistically significant reduction in cell growth. CONCLUSION: These data strongly suggest the usefulness of TRIB3 as a marker for predicting the prognosis of CRC patients, showing a basis for the development of effective treatments for CRC.

Prevalence of chronic obstructive pulmonary diseases in general clinics in terms of FEV1/FVC.

BACKGROUND: The prevalence of chronic obstructive pulmonary disease (COPD) continues to increase all over the world. Nonetheless, COPD is often misdiagnosed in general clinics because of insufficient use of spirometry. OBJECTIVES: To estimate the prevalence of COPD in general clinics in Japan, we performed spirometry to screen patients who consulted general clinics. METHODS: Patients 40 years of age and older who consulted clinics in Nagasaki Prefecture, Japan, for non-respiratory diseases and who met certain inclusion criteria had their airflow limitation measured by spirometry. We defined COPD as forced expiratory volume in the first second (FEV(1)) over forced vital capacity (FVC) (FEV(1)/FVC) of < 70% in patients without active pulmonary disease, including physician-diagnosed asthma. RESULTS: Of the 1424 patients included in the study, 193 (13.6%) showed airflow limitation. Airflow limitation was significantly related to older age, male gender and cumulative pack-years. FEV(1)/FVC in patients with hypertension and chronic hepatitis were significantly lower than in patients without these diseases when adjusted for age, gender and pack-years. CONCLUSIONS: We showed that there are potentially a number of cases with COPD that are undiagnosed by general physicians in Japan. Measuring airflow limitation by spirometry in smokers with coexisting diseases, such as hypertension and chronic hepatitis, may be very beneficial because COPD is thought to be a systemic disease. The distribution of spirometers to general clinics is definitely needed to detect undiagnosed COPD.

[Off-pump coronary artery bypass grafting as standard operation; surgical strategies and results].

We report the clinical results of 799 cases of isolated coronary artery bypass grafting (CABG) performed during the recent 5 years. We performed off-pump CABG (OPCAB) as standard operation, in which arterial grafts were mainly used. The mean number of distal anastomoses was 3.6 +/- 1.4 per patient Four hundred and fifty-five cases (57.0%) were done only with arterial grafts. Bilateral internal thoracic arteries were used in 326 cases. The mean number of saphenous vein grafts was 1.6 +/- 0.8 per patient. Continuous hemodiafiltraion (CHDF) was performed in 22 cases (2.8%) postoperatively. Among the OPCAB cases, 10 cases (1.3%) were converted to on-pump CABG. There were 7 cases (0.9%) of hospital death. The mean length of postoperative hospital stay was 10.2 +/- 5.3 days. The ratio of the patients with left main trunk disease and that of the patients who required postoperative CHDF increased year by year. The mean length of postoperative hospital stay decreased every year, and the reduced length was 2.7 days in the 5 years (8.7+/- 3.6 days in 2007). It is expected that patients who have severe calcified lesions or who are on hemodialysis may increase in the near future. In such cases, CABG rather than percutaneous catheter intervention may be suitable for revascularization. Therefore, not only appropriate choice of treatment strategies, but also accurate surgical techniques may become more importance.

OmpA is an adhesion factor of Aeromonas veronii, an optimistic pathogen that habituates in carp intestinal tract.

AIMS: In the present study, we focused on one of the Aeromonas veronii isolates that exhibited marked adhesion onto carp intestine and studied its membrane-associated proteins for their possible involvement in mucosal adhesion. METHODS AND RESULTS: We isolated a strain of Aer. veronii (CWP11) that exhibited a high degree of temperature-dependent adhesion activity onto carp intestinal tract and studied its adhesion factor. A proteomic analysis of the membrane-associated fraction showed the presence of multiple proteins that were specifically expressed in CWP11 cells cultured at 25 degrees C. Of these, a 30 kDa protein was identified to be OmpA by a mass fingerprint analysis. Cloning and nucleotide sequencing of the ompA region of CWP11 revealed the presence of two tandem ompA homologues (ompAI-ompAII). Escherichia coli that expressed either OmpAI or OmpAII exhibited marked adhesion onto carp intestinal surface. Disruption of ompAI by a homologous recombination technique resulted in marked reduction of the adhesion activity in CWP11. CONCLUSION: The OmpA homologue plays an important role in the adhesion of the Aer. veronii strain onto the surface of intestinal tract. SIGNIFICANCE AND IMPACT OF THE STUDY: We successfully identified an OmpA homologue to be an adhesion factor of Aer. veronii, an optimistic pathogen that habituates in carp intestinal tract.

Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells.

A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation.

Protective effects of 5,6,7,8-tetrahydroneopterin against X-ray radiation injury in mice.

The protective effects of 5,6,7,8-tetrahydroneopterin (NH4) against radiation injury in mice were studied. (C57BL/6xA/J)F1 (B6A) mice received a single whole-body irradiation dose of 200, 400, 700 or 800 cGy of X-rays. NH4 (30 mg/kg body weight) or phosphate-buffered saline (PBS) was injected intraperitoneally into irradiated mice 10 min before and after the irradiation and again after 6 h. All mice which received the 800 cGy radiation+PBS died between 8 and 11 days after the treatment. In contrast, those which also received NH4 demonstrated a significantly prolonged survival time and 40% lived more than 5 months. Total numbers of thymocytes and spleen cells on day 5 post-irradiation were dramatically reduced in line with the radiation dose. The survival was significantly enhanced by NH4 in treated mice. The proliferation of spleen cells in mice stimulated by concanavalin A (Con A) or lipopolysaccharide (LPS) was also greater in NH4 treated mice. The immune response of survivors 5 months after 800 cGy+NH4 treatments, against Con A, LPS, allogenic mouse, and sheep red blood cells had essentially recovered to the levels of normal mice. These results indicate that NH4 had an important role in modifying radiation injury.

Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM.

The onset of NIDDM in obese Zucker diabetic fatty (fa/fa) rats is preceded by a striking increase in the plasma levels of free fatty acids (FFAs) and by a sixfold rise in triglyceride content in the pancreatic islets. The latter finding provides clear evidence of elevated tissue levels of long-chain fatty acyl CoA, which can impair beta-cell cell function. To determine if the triglyceride accumulation is entirely the passive consequence of high plasma FFA levels or if prediabetic islets have an increased lipogenic capacity that might predispose to NIDDM, the metabolism of long-chain fatty acids was compared in islets of obese prediabetic and nonprediabetic Zucker diabetic fatty (ZDF) rats and of lean Wistar and lean ZDF rats. When cultured in 1 or 2 mmol/l FFA, islets of both female and male obese rats accumulated, respectively, 7 and 15 times as much triglyceride as islets from lean rats exposed to identical FFA concentrations. The esterification of [14C]palmitate and 9,10-[3H]palmitate was increased in islets of male obese rats and could not be accounted for by defective oxidation of 9,10-[3H]-palmitate. Glycerol-3-PO4 acyl-transferase (GPAT) activity was 12 times that of controls. The mRNA of GPAT was increased in islets of obese rats. We conclude that, in the presence of comparable elevations in FFA concentrations, the islets of obese prediabetic rats have a higher lipogenic capacity than controls. This could be a factor in their high risk of diabetes.

Preoperative left ventricular function: minimal requirement for successful late results of valve replacement for aortic regurgitation.

Postoperative survival and left ventricular function were studied in 62 patients who underwent aortic valve replacement for isolated, chronic aortic regurgitation between 1978 and 1985. The average follow-up period was 3.8 years. There were three in-hospital and six late deaths. Five (56%) of the nine postoperative deaths were of cardiac-related causes. The mean 7 year survival rate was 83 +/- 5%. Preoperative left ventricular end-systolic volume index was the most important indicator (p less than 0.001) for subsequent cardiac death. The 6.5 year survival rate was 92 +/- 4% for patients with an end-systolic volume index less than 200 ml/m2 compared with 51 +/- 16% for those whose index was greater than 200 ml/m2. None of the 48 patients with an end-systolic volume index less than 200 ml/m2 died of cardiac-related causes. Twenty-three of the 48 patients with an end-systolic volume index less than 200 ml/m2 (Group 1) and 6 of the 12 patients with a higher index (Group 2) underwent repeat catheterization 26 months postoperatively. Preoperative afterload, assessed by end-systolic wall stress, was elevated in both groups, but decreased postoperatively, becoming identical to the afterload in 20 normal control subjects. Although the preoperative ejection fraction was depressed in both groups, the great majority of patients in Group 1, compared with none in Group 2, exhibited normal ejection fraction postoperatively. Thus, in patients who recently underwent surgery for aortic regurgitation, satisfactory late results in both long-term survival and reversal of left ventricular dysfunction were obtained when the preoperative end-systolic volume index was less than 200 ml/m2.

Looped reconstruction of the internal and external iliac arteries in repair of abdominal aortic or iliac artery aneurysm with a bifurcated graft.

AIM: The aim of our study is to describe an original technique of distal anastomosis of a bifurcated graft, coining looped reconstruction, and our preliminary clinical experience. METHODS: This technique has been applied in 16 of 24 distal anastomoses of 12 patients with abdominal aortic aneurysm (AAA) and/or iliac artery aneurysm. Both the internal (IIA) and external iliac arteries (EIA) are transected and anastomosed with end-to-end fashion to reconstruct their continuity, and the limb of a bifurcated graft is anastomosed to the EIA with end-to-side fashion. RESULTS: Operative and in-hospital death, ischemic colitis, or ischemia of the lower extremities including blue toe syndrome has never occurred. All the 28 reconstructed IIAs and EIAs have been patent in 11 patients who could undergo early postoperative computed tomography scans with contrast medium. CONCLUSIONS: The looped reconstruction of the IIA and the EIA in repair of an AAA and/or an iliac artery aneurysm with a bifurcated graft is an anatomically easy and technically simple method.

Stent placement for severe stenosis in the deep femoral artery with the occluded superficial femoral and popliteal arteries.

In both superficial and deep femoral artery involvement, where angioplasty of the former is not suitable or feasible, angioplasty of the latter seems to be the method of choice and is a less invasive and efficient treatment particularly for limb threatening ischemia, an appropriate obstruction morphology provided. The authors describe a case of a 73-year-old man, with a rest pain of the foot and intermittent cyanosis of the toe, who underwent stent placement with transluminal angioplasty for severe stenosis in the deep femoral artery with the occluded superficial femoral and popliteal artery. The patient's ankle brachial index was remarkably increased from 0.25 to 0.61, and the preoperative symptoms were improved.

NeuroD/beta2 gene G-->A polymorphism may affect onset pattern of type 1 diabetes in Japanese.

OBJECTIVE: The majority of type 1 diabetes is considered to be autoimmune with, for the most part, abrupt development. However, type 1 diabetes with slow onset, or the so-called slowly progressive type 1 diabetes or latent autoimmune diabetes in adults, has been recently recognized and is considered to be autoimmune-related. Although some investigators tried to explain the difference in onset pattern by the genetic background, including HLA type, it has not been established thus far. We hypothesized that the difference in onset pattern may relate to regeneration or differentiation of pancreatic beta-cells, and we therefore focused on the NeuroD/BETA2 gene, which encodes a transcription factor for the insulin gene and beta-cell differentiation. RESEARCH DESIGN AND METHODS: We examined the NeuroD/BETA2 gene polymorphism in 105 Japanese type 1 diabetic patients and in 122 nondiabetic Japanese subjects in a case-control study, and we stratified the patients according to their onset pattern and islet-associated autoantibody positivity. RESULTS: Regardless of the existence of islet-associated autoantibody, we found a significant difference in A allele frequency between type 1 diabetic patients with acute-onset type and control subjects. However, no difference was found between type 1 slow-onset diabetic patients and control subjects. CONCLUSIONS: These results support our hypothesis that NeuroD/BETA2 may affect the ability of regeneration of beta-cells, leading to a difference in the onset pattern and clinical course of type 1 diabetes.

Cholesteryl ester transfer protein polymorphism associated with macroangiopathy in Japanese patients with type 2 diabetes.

A polymorphism in the gene for cholesteryl ester transfer protein (CETP) has been reported to be associated with serum cholesterol levels and risk for atherosclerotic vascular diseases, and to clarify the relationship between the gene polymorphism for CETP and macroangiopathy in diabetes mellitus, a cross-sectional study was performed. The subjects of the study were182 Japanese (age: 59.6+/-8.6 years) with type 2 diabetes and no signs of renal dysfunction, 24 of whom had macroangiopathy, and 158 of whom did not. The genotype of the subjects for the TaqIB polymorphism of CETP in intron one was analyzed by using polymerase chain reaction - restriction fragment length polymorphism. Serum CETP levels were significantly higher in the B1/B1 genotype than in the other genotypes (P<0.05). The serum CETP levels were correlated with the serum LDL cholesterol levels (P<0.01), but not with the HDL cholesterol levels. Macroangiopathy was more frequently observed in subjects with the B1/B1 genotype than in the other genotypes (odds ratio=2.953, 95% confidence interval=1.250-6.977, P=0.0136). Logistic regression analysis revealed that the CETP genotype was independently associated with macroangiopathy. The exact mechanism underlying the association remains unknown, but differences in serum CETP levels may be involved.

Determinants for the development of hypertension in adolescents. A 6-year follow-up.

OBJECTIVE: This study was aimed to evaluate the determinants of elevated blood pressure (BP) in adolescents. DESIGN AND METHODS: We retrospectively evaluated the BP and anthropometric data in 419 Japanese students (268 males and 151 females) during high school and university. Their annual health records were analysed for BP, heart rate, height and body weight between the ages of 15 and 21 years. RESULTS: The number of hypertensive students did not vary significantly during the 6 years. Concerning changes in BP categories according to the modified JNCVI classification between the ages of 15 to 21 years, 150 males kept a normal BP (keeping normal BP group); 39 males developed high BP (developing high BP group); 37 males kept high BP (keeping high BP group); and 42 males became normal BP (becoming normal BP group). The majority of females (n = 144, 95.4%) were included in the keeping normal BP group. In male students, both the keeping and becoming normal BP groups, especially the latter, showed a significant decrease in heart rate over the 6 years, while the other two groups showed no change. The height and body weight of each of the four groups showed a significant increase, but the body mass index (BMI) of the males in the becoming normal BP group did not increase over the 6 years. Body weight and BMI at the age of 15 years in the male keeping normal BP group were significantly below that of the other three groups; this difference persisted at the age of 21 years. Furthermore, male university students who showed a BP above 'high-normal' at the age of 21 years exhibited a significantly higher BP, heart rate, body weight and BMI than did the normotensives, when they were high school students. Stepwise regression analysis of the data showed that the best predictors of BP at the age of 21 years were the initial high school BP and BMI levels and changes in BMI and heart rate during the 6-year period for male students. CONCLUSION: Results indicate that the BP and BMI during high school and the changes in BMI and heart rate from high school to university influenced the BP at the age of 21 years in male students. Data indicate that information on the prevention and management of hypertension including weight control should begin early, especially in male adolescents.

The obese gene product, leptin: possible role in obesity-related hypertension in adolescents.

OBJECTIVE: The mechanism of the association between obesity and hypertension is not clear. The recently discovered obese gene product, leptin, the levels of which increase in obese subjects, has been shown to reduce food intake and increase sympathetic nervous system activity in animal studies. The present study was undertaken to elucidate the relationship between blood pressure and factors related to obesity, including leptin, in different age groups. METHODS: The subjects were 348 Japanese male adolescents (15-17 years old) and 165 men (40-59 years old) not taking medication for hypertension, diabetes mellitus or hyperlipidaemia. Height, weight, blood pressure, heart rate, plasma glucose, lipid profiles, serum insulin and leptin levels were measured in the morning after an overnight fast RESULTS: Body mass index (BMI), serum leptin level and the homeostasis model insulin resistance index increased in the order of blood-pressure category (i.e. normotensive < high normal < hypertensive) in both the male adolescents and the middle-aged men. In addition, simple linear regressions revealed that both systolic and diastolic blood pressure correlated significantly with serum leptin and the insulin resistance index in both groups. Even after adjustment for age and BMI, the correlation of mean blood pressure with leptin remained in the obese adolescents (r2 = 0.390, P = 0.02). The heart rate also correlated with leptin in the adolescents (r = 0.18, P< 0.001), but not in the middle-aged subjects (r = 0.04). Even after adjustment for age and BMI in adolescents, serum leptin correlated significantly with heart rate. CONCLUSION: These results suggest a role for leptin in obesity-related hypertension, especially in adolescents.

A potent, long-acting, orally active (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: novel muscarinic M(3) receptor antagonist with high selectivity for M(3) over M(2) receptors.

A novel series of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M(3) receptor selective antagonist 1, to develop a potent, long-acting, orally active M(3) antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(1R)-3, 3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M(3) over M(2) receptors in comparison with the corresponding cyclopentylphenylacetic acid group. However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1-(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M(3) receptors (K(i) = 2.8 nM) over M(2) receptors (K(i) = 530 nM) in a human binding assay and good in vitro metabolic stability in dog and human hepatic microsomes was identified. This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced bronchoconstriction in dogs, and may be useful in clinical situations in which M(3) over M(2) selectivity is desirable.